Study design and participants

The study was embedded in the ongoing Tongji Maternal and Child Health Cohort (TMCHC, registered at clinicaltrials.gov as NCT03099837), which is a population-based prospective cohort study designed to investigate the short- and long- term effect of exposures in the pregnancy on the health of mother-infant pairs. From January 2013 to May 2016, eligible participants were invited to join the TMCHC study at their first prenatal care visit in three research hospitals of Wuhan, China.

Of 7843 pregnant women joined the TMCHC study at 10–16 weeks of gestation who reported the detail information about vaginal bleeding and medical treatments in early pregnancy, after excluding those with polycystic ovarian syndrome (n = 49), test-tube baby (n = 38), twin births (n = 142), triplets (n = 1), miscarriages (n = 160), stillbirths (n = 3), taking Chinese medicine in early pregnancy (n = 216), missing gestational weight gain (n = 49) and information at birth (n = 570), 6615 participants were included to examine the association of maternal vaginal bleeding and progesterone supplementation in early pregnancy with the risk of adverse birth outcomes. 3181 infants’ weight at 12 months of age were followed up and were eligible to investigate the effect of maternal early vaginal bleeding and progesterone supplementation on the growth of infants in the first year of life.

Data collection

At the time of enrolment, all participants completed a structured questionnaire including sociodemographic characteristics (maternal age, ethnology, education, income. etc.), obstetrical information (parity, history of spontaneous and induced abortion, gestational age, last menstrual period, etc.), medical characteristics (history of medical issues, family history of disease, etc.), lifestyle (pre-gravid smoking and drinking habits, etc.) and pre-gravid weight. Maternal height and weight were accurately measured at the same time.

The information about vaginal bleeding and progesterone supplementation were retrospectively collected at enrolment. Participants were instructed to report whether vaginal bleeding occurred, and were asked: “Have you ever taken progesterone for therapeutic purposes since pregnancy?”, if “Yes”, the diagnosis of disease or symptom, the start date and duration of progesterone treatment were recorded. Most of the participants took progesterone for treating vaginal bleeding, and the others took progesterone due to low progesterone level in early pregnancy.

Participants were followed up regularly to have their body weights measured and other health information collected by medical examination. Information on birth outcomes (gestational age at birth, neonatal gender, birthweight, birth length, etc.) were obtained immediately after delivery from the hospital notes. Gestational age was calculated by self-reported last menstrual period at enrolment and confirmed by ultrasound examination at 11–14 weeks of gestation. Pre-pregnancy body mass index (BMI, kg/m2) was calculated from self-reported pre-gravid weight and height measured at the first antenatal visit. Subjects were categorized as underweight (BMI < 18.5), normal weight (18.5 ≤ BMI < 24.0), overweight or obese (BMI ≥ 24.0) accordingly [18]. The gestational weight gain was calculated as the difference between the last measured pre-natal weight and pre-gravid weight.

Outcomes

Preterm and very preterm were defined as a birth prior to 37 and 34 weeks of gestation respectively. LBW was defined as birth weight less than 2500 g regardless of gestational age. SGA was defined as a neonatal birthweight < 10th percentile for gestational age, according to a Chinese neonatal reference [19]. Weight for age z-score (WAZ) was calculated according to 2006 WHO child growth standards [20].

Statistical analysis

Participants were divided into four groups according to the status of vaginal bleeding and treatment in early pregnancy: 1) women without bleeding and any treatment; 2) women without bleeding but taking progesterone; 3) women with bleeding but untreated; 4) women with bleeding and treated with progesterone. The demographics characteristics were compared among four groups. Descriptive statistics were summarized as mean ± SD for continuous variables and frequency (n) and percentages (%) for categorical variables. Differences of characteristics were assessed by one-way analysis of variance (ANOVA) for continuous variables and chi-square test for categorical variables. Multivariable logistic regression was conducted to estimate the independent and combined effect of vaginal bleeding and progesterone supplementation in early pregnancy on offspring outcomes including very preterm, preterm, SGA, LBW, and WAZ < -1 at 12 months of age. In order to investigate whether progesterone therapy in early pregnancy can improve offspring outcomes among women with bleeding, women with bleeding and non-treatment were used as reference group and multivariable logistic regression was performed to calculate the odd ratios (ORs) with 95% Confidence Intervals (95%CIs) for offspring outcomes.

Gestational weight gain, gestational age at delivery, fetal gender, birth weight, birth length, and breast feeding are often strong predictors of offspring’s growth and were therefore considered as potential confounders. However, these variables might lie on the causal pathway from exposure to outcomes. Therefore, we calculated the risk in different models. Model I was adjusted for maternal age, pre-pregnancy BMI, nulliparity, gravidity, history of spontaneous abortion, history of induced abortion, drinking before pregnancy, and gestational age at enrollment. Gestational weight gain and fetal gender were further adjusted in model II to calculate ORs(95%CIs) of very preterm and preterm. Gestational age at delivery, Gestational weight gain, and fetal gender were also adjusted when calculated the ORs (95%CIs) of SGA, and LBW in model II. OR(95%CI) of WAZ < -1 at 12 months of age in model II was also further adjusted for gestational age at delivery, gestational weight gain, fetal gender, birth weight, birth length, and any breastfeeding at 12 months of age. In our study, there were small amounts of missing data in birth length (n = 28), and any breastfeeding at 12 months of age (n = 45), therefore we used multiple imputation to deal with missing data when assessed the association between exposures and infants’ growth, and then presented the results of pooled analyses.

To eliminate the potential effect of maternal pre-pregnancy BMI, age, parity and preterm on offspring outcomes and reinforce the validity of our results, complementary analyses were conducted by multivariable logistic regression to investigate the association of maternal bleeding and progesterone therapy in early pregnancy with offspring outcomes among women with pre-pregnancy BMI 18.5–23.9 kg/m2, age < 35 years, primiparity and term pregnancy (≥ 37 weeks of gestation).

All the statistical analyses were performed using SAS 9.4 software (Statistics Analysis System, USA), and P < 0.05 was considered statistically significant.

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